Kaposi's sarcoma (KS) is a multicellular, angiogenic tumor arising in the setting of immunosuppression, including AIDS and solid organ transplantation. Despite advances in AIDS therapy and prevention, KS remains the most common AIDS-associated malignancy worldwide and carries with it significant morbidity and mortality. The etiologic agent of KS, a gammaherpesvirus known as Kaposi's sarcoma-associated herpesvirus (KSHV, also referred to as HHV8), has been identified in different cell types within KS lesions, including endothelial cells, macrophages and characteristic KS spindle cells that display a unique combination of cell surface markers. Furthermore, the presence of KSHV within circulating B cells, monocytes, and hematopoietic stem cells in patients correlates with the development and severity of KS lesions. Thus, it remains unclear whether cell-free virus infection and subsequent cellular transformation in vivo takes place de novo at the site of tumor formation or, alternatively, whether hematopoietic cells act as primary viral targets from which cell-associated virus migrates to affect the target tissue. This shortcoming in our understanding of KS disease progress is largely due to the absence of an effective in vivo model in which to study the natural history of KSHV infection in the context of an human immune system. To address these issues, the research aims of this research proposal are two-fold: 1) to develop a chimeric animal model involving the engraftment of human hematopoietic tissue into immunodeficient (SCID) mice to allow for the presence of functional human immune and skin tissue compartments, which represent the known cellular targets for KSHV infection and the most common target tissue for KS formation, respectively; 2) to analyze the components of the model following the introduction of KSHV with the application of quantitative PCR, flow cytometry, and immunohistochemistry in an effort to better understand the process of initial infection, dissemination and tumor formation within an in vivo system. An intense research program has been designed to address these aims with the hope of identifying therapeutic targets for the treatment and prevention of this devastating illness.